The 10-, 12-, 14- and 20-fluororetinoic acids and the 10-, 12- and 12,20-difluororetinoic acids have been reported in the literature: Machleidt et al, Justus Liebigs Ann. Chem., 1964, 674: 1; ibid, 1964, 679: 20; ibid, 1965, 681: 21 and U.S. Pat. No. 3,281,440. These compounds were found to have hypocholesterolemic activity. The 10- and 14- fluororetinals were synthesized in 1978 (Asato et al., J. Am. Chem. Soc., 1978, 100: 5957) and were shown to form fluorinated rhodopsin analogs.
The biological activities of the methyl and ethyl esters of 10-, 12- and 14-fluororetinoic acids have been evaluated in a chemically induced mouse papilloma test, and antipapilloma activity greater than the parent non-fluorinated esters were found for ethyl 12-fluororetinoate (Pawson et al., J. Med. Chem., 1979, 22: 1059-1067). Pawson et al have also synthesized (4-methoxy-2, 3,6-trimethylphenyl) nonatetraenoic acids, esters and amides (analogs of retinoic acid) bearing fluorine or the trifluoromethyl group on the polyene side chain (J. Med. Chem., 1979, 22: 1059-1067; ibid, 1981, 24: 101-104), and reported studies of antipapilloma activity.
The use of retinoic acid clinically against dermatoses was reported in 1959, and since that time it has been used in the treatment of acne, psoriasis, ichthyosiform dermatoses, dyskeratoses and various other skin diseases. See The Therapeutic Use of Vitamin A Acid, Proceedings of the International Symposium, Films, Switzerland, Jan. 27-29, 1975; and Acta Dermato-Venereologica, 1975, 55 (Supplement 74), 11-185.
Dietary vitamin A is required for growth, epithelial cell differentiation, vision and reproduction. The mechanism of action of vitamin A in vision is rather well defined, and either retinol or retinal, which are biologically interconvertible, can support vision. Retinoic acid, a natural biological metabolite of retinol, possesses equal growth promoting activity as retinol, but is not active in supporting vision or reproduction. No reports are available on the synthesis of N-retinoyl amino acids.